The life long consequences of developmental events is becoming increasingly apparent. The hippocampus is a critical brain region for integrating external stimuli to promote learning and memory or induce stress and anxiety, and it may serve this role in some capacity as early as the first week of life. The early postnatal period is a sensitive window for the organization of brain sex differences and many hippocampal-related functions and/or associated pathologies exhibit strong gender biases. The goal of this proposal is to explore the novel observation of higher rates of cell genesis in the neonatal male rat hippocampus compared to the female, and an increase in cell genesis by exogenous estradiol treatment. We propose that this period of cell genesis is unique compared to embryonic and adult neurogenesis and we hypothesize that the greater rate in males is the mechanism establishing the larger hippocampus observed in this sex. We also speculate that this early neurogenesis may underlie sex differences in very early learning and enduring consequences of maternal deprivation. We will identify the source of origin of new cells to the hippocampus and determine whether the sex difference and effect of estradiol on new cells are the result of changes in proliferation and/or cell survival. We will further determine whether cell genesis promotes the development of neurons and/or glia. Finally, we will test the hypothesis that sex differences in depolarizing GABA action and enhancement of this response by estradiol is the mechanistic basis for increased cell proliferation and/or survival in the neonatal male hippocampus. We will use BrdU incorporation into new cells, microinjection of cell tracker dye, double label immunofluorescent confocal microscopy, electrophysiology of organotypic slice cultures and single cell calcium imaging to complete nine specific aims that test three distinct hypotheses. Results of this work will provide new therapeutic avenues for prevention, intervention and treatment of developmental neurological disorders and diseases and brain damage. PUBLIC HEALTH RELEVANCE: The hippocampus is a critical brain region regulating cognition and emotionality. Parameters that impact on hippocampal development are essential to understanding adult function and provide insight into the select vulnerability of the hippocampus to damage and disease. The studies proposed here explore the novel observation of increased cell genesis in the newborn male rat hippocampus compared to that of the female. We seek to elucidate the cellular mechanisms mediating this sex difference as a valuable tool for the identification of new targets for therapeutic intervention and prevention.